Utilizing α,β-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRAS inhibitors. Despite this, the precise reaction mechanism between KRAS and covalent inhibitors remains a subject of debate, primarily due to the absence of an appropriate residue capable of deprotonating the cysteine thiol as a base. To uncover this reaction mechanism, we first discussed the chemical reaction mechanism in solvent conditions via density functional theory (DFT) calculation. Based on this, we then proposed and validated the enzymatic reaction mechanism by employing quantum mechanics/molecular mechanics (QM/MM) calculation. Our QM/MM analysis suggests that, in biological conditions, proton transfer and nucleophilic addition may proceed through a concerted process to form an enolate intermediate, bypassing the need for a base catalyst. This proposed mechanism differs from previous findings. Following the formation of the enolate intermediate, solvent-assisted tautomerization results in the final product. Our calculations indicate that solvent-assisted tautomerization is the rate-limiting step in the catalytic cycle under biological conditions. On the basis of this reaction mechanism, the calculated / for two inhibitors is consistent well with the experimental results. Our findings provide new insights into the reaction mechanism between the cysteine of KRAS and the covalent inhibitors and may provide valuable information for designing effective covalent inhibitors targeting KRAS and other similar targets.
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http://dx.doi.org/10.1016/j.csbj.2024.03.027 | DOI Listing |
Cytotechnology
February 2025
Department of Pharmacy, Wuhan Fourth Hospital, No. 473 Hanzheng Street, Qiaokou District, Wuhan, 430030 China.
Unlabelled: Osimertinib has been demonstrated to be effective for improving the prognosis of patients with epidermal growth factor receptor mutation-positive lung cancer. However, osimertinib resistance inevitably emerges throughout the treatment course. This study explored the function and mechanism of long noncoding RNA LINC01278 in osimertinib-resistant NSCLC cells.
View Article and Find Full Text PDFSynthesis (Stuttg)
June 2024
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
The Mitsunobu reaction is one the most widely known reactions in the organic chemistry canon. Despite its fame, some aspects of the mechanism remain poorly understood, 55 years after its initial discovery. This short review collates the findings of several publications focused on the mechanism of the Mitsunobu reaction, highlighting both the current state of knowledge and the remaining missing pieces.
View Article and Find Full Text PDFDrug Des Devel Ther
December 2024
Department of Cardiology, Guang Anmen Hospital, Beijing, People's Republic of China.
Background: Improving angiogenesis in the ischemic myocardium is a therapeutic strategy for preventing, reducing, and repairing myocardial injury of coronary artery disease (CAD). saponins (PNS) have been widely used in the clinical treatment of cardiovascular diseases, demonstrating excellent efficacy, and can potentially improve angiogenesis in the ischemic myocardium. However, the effects of PNS on angiogenesis and its underlying mechanism of action remain unclear.
View Article and Find Full Text PDFFront Cell Infect Microbiol
December 2024
Key Laboratory of Respiratory Disease, People's Hospital of Yangjiang, Yangjiang, China.
Ceftazidime-avibactam (CZA) is one of the effective antibiotics used for the treatment of carbapenem-resistant (CRKP) infections, but its resistance rate has increased recently. Previous studies have focused on the mechanisms of CZA resistance, while its heteroresistance in CRKP remains poorly understood. This study aimed to investigate the characteristics and mechanisms of CZA heteroresistance in CRKP isolates.
View Article and Find Full Text PDFAnn Surg Open
December 2024
From the Department of Surgery, Brigham & Women's Hospital, Boston, MA.
Background: Surgery has seen limited adoption of 360-degree feedback tools, and no current tools evaluate intraoperative performance from a technical, nontechnical, or teaching skill perspective. We sought to evaluate the overall findings and perceived value of a novel 360-degree feedback tool for surgeons from their operating room colleagues.
Methods: The 'intraoperative 360' (i360) combined 3 previously validated scales of surgeon performance.
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